2. Academic Validation
  3. Novel electrophilic amides amenable by the Ugi reaction perturb thioredoxin system via thioredoxin reductase 1 (TrxR1) inhibition: Identification of DVD-445 as a new lead compound for anticancer therapy

Novel electrophilic amides amenable by the Ugi reaction perturb thioredoxin system via thioredoxin reductase 1 (TrxR1) inhibition: Identification of DVD-445 as a new lead compound for anticancer therapy

  • Eur J Med Chem. 2019 Nov 1;181:111580. doi: 10.1016/j.ejmech.2019.111580.
Mirna Jovanović 1,  Daniil Zhukovsky 2,  Ana Podolski-Renić 1,  Ilona Domračeva 3,  Raivis Žalubovskis 4,  Milan Senćanski 5,  Sanja Glišić 5,  Vladimir Sharoyko 2,  Tatiana Tennikova 2,  Dmitry Dar'in 2,  Milica Pešić 6,  Mikhail Krasavin 7
Affiliations

Affiliations

  • 1 Institute for Biological Research "Siniša Stanković", University of Belgrade, 11060, Belgrade, Serbia.
  • 2 Saint Petersburg State University, Saint Petersburg, 199034, Russian Federation.
  • 3 Latvian Institute of Organic Synthesis, Riga, LV-1006, Latvia.
  • 4 Latvian Institute of Organic Synthesis, Riga, LV-1006, Latvia; Institute of Technology of Organic Chemistry, Faculty of Materials Science and Applied Chemistry, Riga Technical University, Riga, LV-1048, Latvia.
  • 5 Laboratory for Bioinformatics and Computational Chemistry, Institute of Nuclear Sciences VINCA, University of Belgrade, P.O. Box 522, 11001, Belgrade, Serbia.
  • 6 Institute for Biological Research "Siniša Stanković", University of Belgrade, 11060, Belgrade, Serbia. Electronic address: camala@ibiss.bg.ac.rs.
  • 7 Saint Petersburg State University, Saint Petersburg, 199034, Russian Federation. Electronic address: m.krasavin@spbu.ru.
PMID: 31400708 DOI: 10.1016/j.ejmech.2019.111580
Abstract

A series of peptidomimetic compounds incorporating an electrophilic moiety was synthesized using the Ugi reaction. These compounds (termed the Ugi Michael acceptors or UMAs) were designed to target the selenocysteine catalytic residue of thioredoxin reductase 1 (TrxR1), a promising Cancer target. The compounds were assessed for their potential to inhibit TrxR1 using human neuroblastoma (SH-SY5Y) cell lysate. Based on this initial screening, six compounds were selected for testing against recombinant rat TrxR1 and in the Insulin assay to reveal low-micromolar to submicromolar potency of these inhibitors. The same frontrunner compounds were evaluated for their ability to exert antiproliferative activity and induce cell death and this activity was compared to the UMA effects on the levels of reactive oxygen and nitrogen species (RONS). Collectively, the UMA compounds class presented itself as a rich source of leads for TrxR1 inhibitor discovery for Anticancer application. Compound 7 (DVD-445) was nominated a lead for further optimization.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-126322
    98.65%, TrxR1 抑制剂
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